Intraventricular dopamine infusion alleviates motor symptoms in a primate model of Parkinson's disease.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
/ pharmacology
Animals
Antiparkinson Agents
/ pharmacology
Disease Models, Animal
Dopamine
/ administration & dosage
Dopamine Agonists
/ pharmacology
Dyskinesia, Drug-Induced
/ drug therapy
Infusions, Intraventricular
Levodopa
/ analogs & derivatives
Macaca
Male
Motor Activity
/ drug effects
Parkinson Disease
/ drug therapy
Parkinsonian Disorders
/ drug therapy
Pilot Projects
Continuous dopaminergic stimulation
Dopamine in anaerobia
Motor fluctuations with dyskinesia
Neurosurgical treatment
Parkinson's disease
Journal
Neurobiology of disease
ISSN: 1095-953X
Titre abrégé: Neurobiol Dis
Pays: United States
ID NLM: 9500169
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
22
01
2020
revised:
24
02
2020
accepted:
18
03
2020
pubmed:
25
3
2020
medline:
13
4
2021
entrez:
25
3
2020
Statut:
ppublish
Résumé
Continuous compensation of dopamine represents an ideal symptomatic treatment for Parkinson's disease (PD). The feasibility in intracerebroventricular administration (i.c.v.) of dopamine previously failed because of unresolved dopamine oxidation. We aim to test the feasibility, safety margins and efficacy of continuous i.c.v. of anaerobic-dopamine (A-dopamine) with a pilot translational study in a non-human primate model of PD. Continuous and circadian i.c.v. of A-dopamine was administered through a micro-pump connected to a subcutaneous catheter implanted into the right frontal horn of 8 non-human primates treated with 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP). A-dopamine was assessed at acute doses previously reported for dopamine as well as evaluating the long term therapeutic index of A-dopamine in comparison to anaerobically prepared L-dopa or methyl ester L-dopa. Over 60 days of a continuous circadian i.c.v. of A-dopamine improved motor symptoms (therapeutic index from 30 to 70 mg/day) without tachyphylaxia. No dyskinesia was observed even with very high doses. Death after 1 to 10 days (without neuronal alteration) was only observed with doses in excess of 160 mg whereas L-dopa i.c.v. was not effective at any dose. The technical feasibility of the administration regimen was confirmed for an anaerobic preparation of dopamine and for administration of a minimal infusion volume by micro-pump at a constant flow that prevented obstruction. Continuous circadian i.c.v. of A-dopamine appears to be feasible and shows efficacy without dyskinesia with a safe therapeutic index.
Sections du résumé
BACKGROUND
Continuous compensation of dopamine represents an ideal symptomatic treatment for Parkinson's disease (PD). The feasibility in intracerebroventricular administration (i.c.v.) of dopamine previously failed because of unresolved dopamine oxidation.
OBJECTIVES
We aim to test the feasibility, safety margins and efficacy of continuous i.c.v. of anaerobic-dopamine (A-dopamine) with a pilot translational study in a non-human primate model of PD.
METHODS
Continuous and circadian i.c.v. of A-dopamine was administered through a micro-pump connected to a subcutaneous catheter implanted into the right frontal horn of 8 non-human primates treated with 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP). A-dopamine was assessed at acute doses previously reported for dopamine as well as evaluating the long term therapeutic index of A-dopamine in comparison to anaerobically prepared L-dopa or methyl ester L-dopa.
RESULTS
Over 60 days of a continuous circadian i.c.v. of A-dopamine improved motor symptoms (therapeutic index from 30 to 70 mg/day) without tachyphylaxia. No dyskinesia was observed even with very high doses. Death after 1 to 10 days (without neuronal alteration) was only observed with doses in excess of 160 mg whereas L-dopa i.c.v. was not effective at any dose. The technical feasibility of the administration regimen was confirmed for an anaerobic preparation of dopamine and for administration of a minimal infusion volume by micro-pump at a constant flow that prevented obstruction.
CONCLUSION
Continuous circadian i.c.v. of A-dopamine appears to be feasible and shows efficacy without dyskinesia with a safe therapeutic index.
Identifiants
pubmed: 32205254
pii: S0969-9961(20)30121-2
doi: 10.1016/j.nbd.2020.104846
pii:
doi:
Substances chimiques
Antiparkinson Agents
0
Dopamine Agonists
0
Levodopa
46627O600J
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
9P21XSP91P
levodopa methyl ester
M30686U4X4
Dopamine
VTD58H1Z2X
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
104846Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.